title: Screening of monoclonal antibody formulations based on high-throughput thermostability and viscosity measurements: design of experiment and statistical analysis.
abstract: The purpose of this study was to demonstrate the utility of combining a design of experiment (DOE) approach with high-throughput formulation screening to identify the main factors affecting protein thermostability and solution viscosity. The optimization of buffer compositions was guided by statistical analysis of the data to obtain the targeted combination of low viscosity and high thermostability. Different monoclonal antibody (mAb) formulation variables were evaluated in the study to achieve optimization of two parameters: (i) thermostability characterized by temperature of hydrophobic exposure and (ii) viscosity. High-throughput measurements were employed to characterize both parameters. The significance of each factor and the two-way interactions between them was studied by multivariable regression analysis. An experimental design was used to estimate the significance of all factors, including interaction effects. The range of optimal buffer compositions that maximized thermostability and minimized viscosity of a mAb formulation was determined. The described high-throughput methods are well suited for characterization of multiple protein formulation compositions with minimized resources such as time and material. The DOE approach can be successfully applied to the screening of mAb formulations early in the development lifecycle.
authors.affiliation: Process & Product Development, Amgen Inc., Seattle, Washington, 98119.
authors.forename: Feng
authors.initials: F
authors.lastname: He
authors.forename: Christopher E
authors.initials: CE
authors.lastname: Woods
authors.forename: Egor
authors.initials: E
authors.lastname: Trilisky
authors.forename: Keith M
authors.initials: KM
authors.lastname: Bower
authors.forename: Jennifer R
authors.initials: JR
authors.lastname: Litowski
authors.forename: Bruce A
authors.initials: BA
authors.lastname: Kerwin
authors.forename: Gerald W
authors.initials: GW
authors.lastname: Becker
authors.forename: Linda O
authors.initials: LO
authors.lastname: Narhi
authors.forename: Vladimir I
authors.initials: VI
authors.lastname: Razinkov
mesh_terms: D000911:Antibodies, Monoclonal / Q000737:chemistry*; D002021:Buffers; D004355:Drug Stability; D005079:Excipients / Q000737:chemistry*; D057166:High-Throughput Screening Assays / Q000379:methods; D007074:Immunoglobulin G / Q000737:chemistry*; D055550:Protein Stability; D013696:Temperature; D014783:Viscosity
chemical_list: D000911:Antibodies, Monoclonal; D002021:Buffers; D005079:Excipients; D007074:Immunoglobulin G
keywords: Design of experiment; Excipients; High throughput; Monoclonal antibodies; Preformulation; Protein formulation; Thermal analysis; Viscosity